同源重组修复(HR)是DNA损伤修复中的一条重要途径。基于化学干预HR策略的抗癌创新药物研究备受关注。最新研究指出，DNA解旋酶BLM在HR中扮演重要角色。但是，以BLM为靶点的药物化学研究尚未开展。申请人前期研究发现了选择性靶向BLM的新型小分子抑制剂A1-22，其对BLM高表达的癌细胞毒性更强。该化合物通过抑制BLM活性，引起HR水平异常上调和DNA损伤加剧，进而抑制癌细胞增殖。由此申请人提出基于靶向BLM介导的HR途径发展抗癌新策略的研究思路。本项目拟在已有基础上，基于A1-22结构，设计、合成并构建新化合物库；完善活性评价与机制研究体系；总结构效关系并对结构进行合理优化；深入研究化合物与靶点以及靶点与底物核酸的相互作用，揭示化学干预BLM功能下影响HR和抑制肿瘤生长的新机制；发现活性高、成药性好的靶向BLM的抗癌先导化合物。为发现抗癌药物新靶点和发展抗癌新策略提供理论和实验依据。

Homologous recombination repair (HR) is an important approach in DNA damage repair. The research on anti-cancer innovative drugs via chemical intervening HR to suppress tumor has attracted wide attention. Recent research indicated that BLM helicase played a crucial role in HR, but the relevant medicinal chemistry research had not been carried out yet. In our previous studies, a novel BLM inhibitor A1-22 was discovered by screening our compound library and more toxic to BLM high expression cancer cells. it was shown that HR level up-regulated abnormally when the BLM activity was inhibited by A1-22, which led to seriously DNA damage and tumor proliferation inhibition. Therefore, the applicant suggested that targeting HR pathway mediated by BLM had the potential to be a new way in cancer therapy. On the basis of previous research, the project plan to achieve the following research work and goals: 1) to design and synthesize a series of novel active small molecules and build the compounds library based on the structure of A1-22. 2) to perfect the activity evaluating and mechanism studying system. 3) to summarize the structure-activity relationship and optimize molecular structure. 4) to further study the interaction between selected compounds and BLM，BLM and its DNA substrates. 5) to reveal the possible new mechanism of chemical intervening BLM function to affect homologous recombinant repair and tumor growth. 6) to identify good inhibitors with high activity and good druggability. This project might provide a useful theoretical and experimental basis for the discovery of new target for drugs and the development of new strategies to treat cancer.